Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=1[CH:21]([CH3:40])[C:22]([C:28]1[CH:39]=[CH:38][C:31]2[N:32]([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:30]=2[CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24].C(N(CC)CC)C.C1N2CCN(CC2)C1>CN(C=O)C.O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([O:20][C:18]2[CH:17]=[CH:16][C:15]([CH:21]([CH3:40])[C:22]([C:28]3[CH:39]=[CH:38][C:31]4[N:32]([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:30]=4[CH:29]=3)([OH:27])[C:23]([F:24])([F:25])[F:26])=[C:14]([Cl:13])[CH:19]=2)=[N:11][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)n(C)c(=O)n4C)C(F)(F)F)c(Cl)c2)nc1Cl
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2,6-dichloronicotinate (CAS Reg. No. 65515-28-8, 20 mg) in DMF (0.5 ml) was added 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 40 mg), followed by triethyl amine (0.02 ml). The mixture was stirred for 10 min, then DABCO (2 mg) was added. The mixture was stirred at room temperature over night. Water was added to the mixture and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 1:2 EtOAc/heptane) to give the title compound (55 mg) as white foam. MS (m/e)=585.9 [M+H+].
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([Br:12])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:15](N)=[O:16].C(O)C.[OH-:21].[K+].[OH2:23]>>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:13][CH3:14])[N:5]=[N:4][C:3]([C:15]([OH:16])=[O:21])=[C:2]2[OH:23]
Reactant: COc1cc2nnc(C(N)=O)c(N)c2cc1Br
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: COc1cc2nnc(C(=O)O)c(O)c2cc1Br
Temperature: 75 °C

Procedure:
A 1 L flask was charged with 4-amino-6-bromo-7-methoxycinnoline-3-carboxamide (Method 15) (30 g, 101 mmol) and ethanol (650 ml). A suspension of potassium hydroxide (100 g, 1782 mmol) in water (350 ml) was added to the reaction and the mixture was stirred at reflux for 9 days. The reaction was then cooled and filtered through a pad of Celite which was washed with water (˜250 mL). The resulting filtrate was conc. in vacuo to remove the ethanol and the resulting aqueous solution was acidified with conc. HCl to pH 3. A precipitate formed which was collected by vacuum filtration. The resulting solid was suspended in 1.4 L of ethanol, heated to 75° C. for 15 minutes, and cooled to room temperature which provided the crude precipitate which was collected by vacuum filtration. The filter cake was washed with ethanol (˜200 mL) and diethyl ether (˜200 mL) to yield the title compound as a brown solid which was used without further purification (26.0 g, 86%). 1HNMR: 14.60 (m, br, 2H), 8.35 (s, 1H), 7.23 (s, 1H), 4.08 (s, 3H); m/z: 310.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:20](OC1C=CC(Cl)=C(Cl)C=1Cl)(=[O:25])[CH2:21][C:22]([O-])=[O:23]>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:12]2[CH:17]=[CH:16][N:15]3[C:20](=[O:25])[CH2:21][C:22](=[O:23])[N:18]=[C:14]3[CH:13]=2)=[O:19])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccnc(N)c2)n1
Reactant: O=C([O-])CC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1csc(NC(=O)C2=CC3=NC(=O)CC(=O)N3C=C2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
N4-[4-(tert-Butyl)-1,3-thiazol-2-yl]-2-aminoisonicotinamide (200 mg, 0.724 mmol) was added with xylene (20 ml) and trichlorophenyl malonate (370 mg, 0.796 mmol) and refluxed by heating at 130° C. The reaction solution was stirred for 1 hour, then returned to room temperature and concentrated under reduced pressure. The resulting orange crystals was taken by filtration, washed with chloroform, dried under reduced pressure to obtain 209 mg (84%) of the title compound as orange crystals without purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CS(C)=O>[ClH:21].[ClH:21].[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:18][CH2:19][CH2:20][Cl:21])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Fc1ccc(CN2CCNCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cl
Product: Fc1ccc(CN2CCN(CCCCl)CC2)cc1
Yield: 179.2 %

Procedure:
The procedure described in Example 1(a) was followed, using 32.8 g of 1-(4-fluorobenzyl)piperazine, 30.0 g of potassium hydroxide, 100 ml of dimethyl sulfoxide and 27.0 g of 1-bromo-3-chloropropane. Work-up, as described above, gave 35.2 g (61% of theory) of 1-(4-fluorobenzyl)-4-(3-chloropropyl) piperazine dihydrochloride as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=4)[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]O>>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=4)[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CN(C)CCO
Product: CN(C)CCOc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 74 %

Procedure:
Obtained in 74% yield by an analogous method to Example 860, starting from 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol and 2-(dimethylamino)ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[N:12][C:11](Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]([CH3:29])([O-:28])[CH3:27].[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=[CH:75][CH:76]=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:26]([O:28][C:6]([N:7]1[CH2:76][CH2:75][N:12]([C:11]2[CH:10]=[N:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])=[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[N:12]=2)[CH2:13][CH2:8]1)=[O:5])([CH3:29])([CH3:27])[CH3:25]
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1OCc1cccc(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1OCc1cccc(Cl)c1
Temperature: 80 °C

Procedure:
[5-Bromo-3-(3-chloro-benzyloxy)-pyrazin-2-yl]-carbamic acid tert-butyl ester I-3p (2.18 g, 5.3 mmol), pperazine-1-carboxylic acid tert-butyl ester (1.18 g, 6.3 mmol), sodium tert-butoxide (0.71 g, 7.4 mmol), racemic BINAP (196 mg, 315 μmol), and tris(benzylideneacetone)dipalladium (96.5 mg, 105 μmol) were placed in a vial equipped with a septum cap. The vial was evacuated and backfilled with dry nitrogen three times, and toluene (11 mL) added. The mixture was heated to 80° C. for 2 h then cooled to room temperature. Resulting suspension was transferred to a flask with CH2Cl2 and concentrated in vacuo to an amber oily solid. Purification by silica gel column (hexanes/EtOAc 7:3) gave the title compound I-3q as a yellow foam (560 mg, 25% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[C:12]([OH:14])=O)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[C:29]1([NH2:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[O:36]1[C:41]2=[CH:42][CH:43]=[CH:44][C:40]2=[CH:39][CH:38]=[CH:37]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:12](=[O:14])[N:35]([C:37]2[O:36][C:41]3=[CH:42][CH:43]=[CH:44][C:40]3=[CH:39][CH:38]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: c1coc2cccc-2c1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(CC(C(=O)O)c2ccc(Br)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(Br)cc2)cc1
Reaction time: 14 h
Yield: 65.6 %

Procedure:
To a stirred suspension of 4-[2-(4-bromo-phenyl)-2-carboxy-ethyl]benzoic acid methyl ester (0.4 g, 1.10 mmol) in anhydrous CH2Cl2 (10 mL), was added oxalyl chloride (0.28 g, 2.7 mmol) at room temperature. The reaction mixture was stirred for 14 h, concentrated under reduced pressure and coevaporated with CH2Cl2 (2×10 mL. The crude material was dried under vacuum for 3 h. The crude acid chloride (0.4 g, 1.04 mmol) was treated with 4-benzofuran phenyl amine (Step E above, 0.26 g, 1.25 mmol) and N,N-diispropylethylamine (0.6 mL, 3.12 mmol) in CH2Cl2 at 0° C. The resulting mixture was stirred for 14 h at room temperature and concentrated under reduced pressure. The residue was treated with MeOH and the precipitate was filtered and washed with cold MeOH to give 4-[2-(4-benzofuran-2yl-phenylcarbamoyl)-2-(4-bromo-phenyl)-ethyl]-benzoic acid methyl ester as a brownish solid (0.4 g, 69%): 1H NMR (300 MHz, CDCl3): δ 7.82 (d, J=8.1 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 7.38-7.47 (m, 5H), 7.09-7.20 (m, 7H), 6.87 (s, 1H), 3.81 (s, 3H), 3.53-3.64 (m, 2H), 3.0 (dd, J=6.6, 12.9 Hz, 1H); LC-MS m/z=554 [C31H42NBrO4+H]+; TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (2:1); Rf=0.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.P([S-])(OCC)(OCC)=[S:24]>C(OCC)(=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[C:11](=[S:24])[NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1ccc(C(C#N)CCc2cccc(Br)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(CCc2cccc(Br)c2)C(N)=S)cc1
Yield: 73 %

Procedure:
By a reaction in the same manner as in Example 178a and using the compound (3.94 g, 11.0 mmol) obtained in Example 181a, 4M hydrogen chloride-ethyl acetate solution (40 mL) and O,O-diethyl dithiophosphate (2.43 mL, 14.5 mmol), the title compound (3.15 g, 73%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]1([C:7]2([CH2:11][OH:12])[CH2:10][O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH:1]1([C:7]2([CH:11]=[O:12])[CH2:8][O:9][CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCC1(C2CCCCC2)COC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1(C2CCCCC2)COC1
Temperature: 25 °C

Procedure:
3-Cyclohexyl-3-hydroxymethyloxetane (7.0 g) was dissolved in dry dichloromethane (20 ml) and added dropwise to a mixture of oxalyl chloride (1.1 eq, 4 ml) in dry dichloromethane (15 ml). At -70° C. a solution of dimethyl sulphoxide (7.15 ml) in dichloromethane (10 ml) was added. After stirring at -70° C. for 30 minutes triethylamine (29 ml) was added over 30 minutes. The reaction mixture was allowed to warm up to room temperature over a period of 3 hours and then quenched in water. Extraction with dichloromethane, followed by washing with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine and drying over magnesium sulphate gave a solution which was evaporated to give 3-cyclohexyl-3-formyloxetane as a colourless oil.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[O:17][CH2:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21](Cl)=[N:22][O:23][CH3:24]>CCOCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[O:17][CH2:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[N:22][O:23][CH3:24]
Reactant: c1c[nH]cn1
Reactant: CON=C(Cl)c1ccccc1COc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(c1ccccc1COc1cccc(Cl)c1)n1ccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
N,N-Dimethylformamide (3 ml) and 60% sodium hydride (0.16 g, 3.9 mmol) were added to imidazole (0.27 g, 3.9 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, 2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl chloride (0.40 g, 1.3 mmol) was added, and the mixture was stirred at 110° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 1-[2-(3-chlorophenoxymethyl)-α-methoxyiminobenzyl]imidazole (0.29 g, 65.3%) as colorless crystals. mp. 96.5-97.5° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:58]1([CH2:61][N:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:23]=[C:24]([F:33])[C:25]([C:26]([N:65]5[CH2:66][CH2:67][N:62]([CH2:61][CH:58]6[CH2:60][CH2:59]6)[CH2:63][CH2:64]5)=[O:28])=[CH:29][C:30]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CN(CC2CC2)CCN1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCN(CC3CC3)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 1-(cyclopropylmethyl)piperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.07 (d, J=4.55 Hz, 2 H) 0.45 (d, J=8.08 Hz, 2 H) 0.75-0.87 (m, 1 H) 1.47-1.77 (m, 6 H) 1.92 (br. s., 2 H) 2.20 (d, J=6.57 Hz, 2 H) 2.32-2.43 (m, 2 H) 3.22-3.31 (m, 2 H) 3.64 (br. s., 2 H) 3.88 (s, 3 H) 4.06 (t, J=13.77 Hz, 3 H) 4.70-4.84 (m, 1 H) 6.97 (d, J=6.06 Hz, 1 H) 8.04 (s, 1 H) 8.16 (d, J=11.87 Hz, 1 H) 8.28 (s, 1 H). [M+H] calculated for C29H36F3N7O3, 588; found 588.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:28]([O:35][C:36](=[O:39])[CH2:37]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36](=[O:39])[CH2:37][N:14]([S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:12])=[O:13])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(S(=O)(=O)N(CC(=O)OCc2ccccc2)c2ccc(N3CCC(=O)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 242) and benzyl-2-bromoacetate according to the procedure of Example 251 as an orange gum; 1H NMR (300 MHz, CDCl3) δ 2.53 (t, J=6.06 Hz, 4H), 3.59 (t, J=6.00 Hz, 4H), 3.79 (s, 3H), 3.93 (s, 3H), 4.50 (s, 2H), 5.13 (s, 2H), 6.78–6.87 (m, 2H), 7.07–7.10 (m, 2H), 7.15 (d, J=2.1 Hz, 1H), 7.27–7.37 (m, 7H); MS (ES) m/z: 539.0 (MH+); HRMS found for C28H30N2O7S (MH+): 539.1842.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24])#[CH:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[C:19]([C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][C:27]=1[F:28])#[CH:20]
Reactant: C#Cc1cc(N)ccc1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#Cc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 71.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 204 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 211 mg of 3-ethynyl-4-fluoroaniline, and 195 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.126 ml of pyridine and 3 ml of N,N-dimethylformamide. 200 mg of N-(3-ethynyl-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29].C1(N2CCC3C=CC(OC4N=CC(N5CCC5=O)=CC=4)=CC=3CC2)CCC1>>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:26]5[CH2:27][CH2:28][O:24][C:25]5=[O:29])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: O=C1NCCO1
Agent: O=C1CCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Product: O=C1OCCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
Example 220 (E220) was prepared from 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and 1,3-oxazolidin-2-one using the method described for Example 219 (E219); MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[CH3:18].COC(C)(C)C>C(#N)C>[Br-:1].[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N+:14]2[C:13]([CH3:12])=[C:17]([CH3:18])[S:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Cc1ncsc1C
Solvent: CC#N
Solvent: COC(C)(C)C
Product: Cc1sc[n+](CC(=O)c2ccc(O)cc2)c1C
Product: [Br-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
The neat mixture of 2-bromo-4′-hydroxyacetophenone (3 g, 15 mmol) and 4,5-dimethylthiazole (1.71 g, 15 mmol) was heated at 110° C. for 3 hrs. It was dissolved in acetonitrile (15 mL) and cooled to room temperature. Tert-butyl methyl ether (5 mL) was added and the reaction mixture kept at room temperature overnight. The product crystallized was filtered, washed well with a mixture of acetonitrile and tert-butyl methyl ether (1:1, v/v) and dried. It was recrystallized from a mixture of acetonitrile, ethyl alcohol and tert-butyl methyl ether. Yield: 3.18 g (64%); mp. 245–247° C. (dec.).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:21][OH:22])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[CH:4][N:3]=1.C(C1C=CC(C2ON=C(C3C=CC(C=O)=NC=3)N=2)=CC=1)C(C)C.C(C1C=CC(C2ON=C(C3N=CC([CH2:67][NH:68][CH:69]4[CH2:72][CH:71]([C:73]([OH:75])=[O:74])[CH2:70]4)=NC=3)N=2)=CC=1)C(C)C>>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:67][NH:68][C@@H:69]4[CH2:72][C@H:71]([C:73]([OH:75])=[O:74])[CH2:70]4)=[N:3][CH:4]=3)=[N:12][N:11]=2)=[CH:14][CH:15]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cc1ccc(-c2nnc(-c3ccc(Cl)nc3)o2)cc1
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(CNC4CC(C(=O)O)C4)cn3)no2)cc1
Agent: CC(C)Cc1ccc(-c2nc(-c3ccc(C=O)nc3)no2)cc1
Product: CC(C)Cc1ccc(-c2nnc(-c3ccc(CN[C@H]4C[C@@H](C(=O)O)C4)nc3)o2)cc1

Procedure:
The title compound was prepared from 2-chloro-5-[5-(4-isobutylphenyl)-1,3,4-oxadiazol-2-yl]pyridine by procedures analogous to those described in Preparations (5C-5D) and Examples (1A-1B) for the preparation of 5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridine-2-carbaldehyde and 3-({5-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrazin-2-ylmethyl}-amino)-cyclobutanecarboxylic acid, respectively.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[NH4+:38].C(O)(=O)C>O>[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]2[NH:38][C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [NH4+]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc(OCc3ccccc3)cc2)[nH]c1-c1ccc(C)cc1
Yield: 46.9 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (44.9g), 4-benzyloxybenzaldehyde (61.0 g) and ammonium acetate (147 g) were added to acetic acid (400 ml) and themixturewas refluxed under heating for 17 hr. Water (1.5 L) was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethyl acetate and ether to give ethyl 2-(4-benzyloxyphenyl)-5-(4-methylphenyl)-imidazole-4-carboxylate (36.9 g), melting point 168-170° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1ccc2[nH]ccc2c1
Agent: Cl
Product: CN(Cc1ccc2[nH]ccc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 38.8 %

Procedure:
According to the procedure of Example 35g (1H-indol-5-yl-methyl)-methyl-amine (257 mg, 1.62 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (312 mg, 1.23 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (172 mg, 39%) as a white solid and a mixture of amide rotomers: 1H NMR (300 MHz, DMSO-d6) δ 11.06-11.05 (m, 1H), 10.63-10.61 (m, 1H), 8.36-8.34 (m, 1H), 8.06 (s, 1H), 7.56-7.19 (m, 5H), 7.02-6.96 (m, 1H), 6.38 (s, 1H), 4.84-4.65 (m, 2H), 3.06-2.85 (m, 5H), 2.55-2.52 (m, 2H); ESI MS m/e 361 [C21H20N4O2+H]+.